The overall objective of the study is to characterize the drug-drug interactions of a series of model centrally-acting drugs following various morphine treatments (morphine dependent, acute morphine, morphine withdrawal) and to investigate the mechanisms by which such interactions are manifested. For the next project period, work will focus on cocaine, diazepam, and ethanol. Studies will include assessment of skeletal muscle coordination following the administration of diazepam or ethanol to morphine- and sham-treated rats, and assessment of changes in body temperature following administration of ethanol to morphine- and sham-treated animals. To understand the basis for the altered pharmacological responses (observed in previous studies) in morphine-treated animals following the administration of diazepam, cocaine, or ethanol, various mechanisms will be investigated. First, the effect of phenobarbital (inducer of drug biotransformation) or SKF 525-A (inhibitor of drug biotransformation) on cocaine-induced upon field locomotor activity and rotored performance following diazepam will be investigated. Secondly, disposition of diazepam, cocaine, and ethanol in brain and plasma will be measured in the various morphine-treated groups. Finally, calcium concentrations in various brain parts (including subcellular distribution) will be investigated following the administration of diazepam, cocaine, or ethanol to morphine- and sham-treated rats.